MCFD2, an EF-hand domain-containing protein, is crucial as it forms a calcium-dependent heteromeric complex with LMAN1 (also known as ERGIC-53). This LMAN1-MCFD2 complex functions as a cargo receptor in the endoplasmic reticulum (ER)-to-Golgi transport pathway for several glycoproteins, including coagulation factors V and VIII (FV/FVIII) and α1-antitrypsin (AAT) [2,3,4,5]. Genetic studies of MCFD2 have provided insights into diseases such as combined deficiency of FV and FVIII (F5F8D) and AAT deficiency-related liver and lung diseases.

In MCFD2-deficient mice, plasma levels of FV and FVIII are reduced, with levels even lower than those in LMAN1-deficient mice, mirroring the situation in human patients [3]. This indicates a significant role of MCFD2 in the efficient secretion of FV and FVIII. Additionally, male MCFD2-deficient mice also show decreased plasma levels of AAT, with comparable AAT accumulation in hepatocyte ER as in LMAN1-deficient mice, suggesting a role for MCFD2 in the efficient ER exit of AAT [3]. RNAi targeting MCFD2 in mice can promote anticoagulation, as it leads to reduced expression of MCFD2, prolonged APTT, and decreased FVIII activity [1].

In conclusion, MCFD2 is essential for the ER-to-Golgi transport of key glycoproteins like FV, FVIII, and AAT. Studies using MCFD2-deficient mouse models have provided valuable insights into its role in F5F8D and AAT-related diseases, highlighting its potential as a target for developing anticoagulant drugs and treatments for AAT deficiency.